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Depression as Deficient Serotonin


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Depression is a state of persistent low mood, often with low self-esteem and a loss of interest in activities and experiences. It affects hundreds of millions of people worldwide; this pervasive condition affects the quality of life through emotional, cognitive, behavioral, and physical symptoms. Depression is the leading cause of disability, and can lead to suicide. [13, 15]

Physicians often prescribe selective serotonin reuptake inhibitors (SSRIs) to treat depression. These drugs work by preventing the reuptake of serotonin back into the synapse of a neuron, theoretically leaving more serotonin to bind to receptors. [1, 14] However, SSRIs are not effective for everyone, and many people experience adverse side effects. [2, 6, 10] Thus, practitioners and patients alike may search for other solutions. The underlying idea of targeting serotonin and the communication system of neurotransmitters by natural means may offer an alternative or complementary option.


Serotonin is an inhibitory neurotransmitter synthesized from tryptophan, an amino acid. It is found in the central nervous system (CNS), blood platelets, and most abundantly in the gut. Serotonin is involved in many body functions, including mood, sleep (as the precursor to melatonin), pain perception, hormone secretion, food intake, and cognitive function. This inhibitory neurotransmitter helps to promote calm, relaxation, and a sense of wellbeing. Serotonin also acts as a neuromodulator, able to reduce the release of glutamate, the main excitatory neurotransmitter, as well as stimulate the release of the main inhibitory neurotransmitter GABA. [4]

If the level or function in the body is insufficient, serotonin will not be able to work optimally in regulating excitation or stimulating GABA. Without serotonin’s modulation and inhibitory effects, excitatory neurotransmission (glutamate, dopamine, norepinephrine, epinephrine) may be in excess, causing over-excitation that could result in anxiety, irritability, poor memory, lack of focus, and poor sleep. People with low serotonin levels may experience increased depression, as well as anxiety, pain perception, carbohydrate cravings, and insomnia due to the low serotonin and GABA activity. Sufficient levels of serotonin in the body may help maintain balance between excitation/energy and inhibition/relaxation. [8]


Individuals with depression and low serotonin may benefit from supplementation to support serotonin. 5-HTP is a popular supplement for this use, as it is the direct precursor to serotonin in the serotonin biosynthetic pathway. Supplemental 5-HTP readily crosses the blood-brain barrier and increases CNS synthesis of serotonin. 5-HTP supplementation has been shown to be effective in reducing anxiety, increasing calmness, and promoting a sense of well-being. [1]

Additionally, some individuals may benefit from a supplement containing myo-inositol. Inositol is an isomer of glucose that we consume naturally in our diets. In the body, inositol is found in cell membranes. Inositol helps with the maintenance and effectiveness of cell signaling as part of the second messenger system. [7, 10] Inositol’s functions in cell communication is important because this second messenger system is associated with neurotransmitter pathways and receptors, including serotonin. Inositol may modulate the interaction between neurotransmitters, drugs, receptors, and signaling proteins. [3, 7] Inositol may also reverse desensitization of serotonin receptors, a common effect of SSRIs. [10] Research has shown that inositol may be beneficial for people with depression and bipolar depression, as well as anxiety, panic disorders, OCD, and other mood concerns. [3, 7, 10, 12]

St. John’s wort is an herb commonly used for depression. St. John’s wort inhibits the reuptake of neurotransmitters such as serotonin, GABA, and dopamine, leaving more of these neurotransmitters available for potential use. This herb can also increase neurotransmitter sensitivity. Better neurotransmission means that there could be more potential for the mood regulation and calming effects of serotonin and GABA. [9]

Individuals with depression may also consider a supplement containing vitamin B6. Vitamin B6 has a variety of positive health effects due to its involvement with neurotransmitters. In the active form of pyridoxal-5-phosphate, vitamin B6 is a cofactor in the serotonergic pathway. B6 supplementation can increase serotonin and dopamine, thus increasing the calming, pain-inhibiting, and pleasurable effects of these neurotransmitters. [5] Vitamin B6 has been found to decrease the severity of depression, as well as anxiety, headaches, and pain. [5, 16] Additionally, vitamin B6 may be even more effective in combination with calcium or magnesium supplementation. [5, 11]

Overall, serotonin plays a major role in maintaining balance within the body and regulating a variety of functions associated with depression. Before implementing or altering an intervention for depression, it is essential to first assess neurotransmitter levels to reveal any imbalances or deficiencies present. After introducing an appropriate intervention, such as 5-HTP supplementation, allowing adequate time for levels to replenish, it is also important to retest neurotransmitter levels to determine the effectiveness of the intervention in increasing serotonin and improving depression, and making any necessary adjustments to the individual’s therapy.

Following this model of testing and retesting, along with safe, effective therapies, may help people with depression understand underlying imbalances related to their experience, and offer evidence-based therapies that may be effective in managing depression and improving their quality of life.



1. Alramadhan, E., Hanna, M. S., Hanna, M. S., Goldstein, T. G., Avila, S. M., & Weeks, B. S. (2012). Dietary and botanical anxiolytics. Medical Science Monitor, 18(4), RA40-RA48.

2. Camfield, D. A., Sarris, J., & Berk, M. (2011). Nutraceuticals in the treatment of obsessive compulsive disorder (OCD): a review of mechanistic and clinical evidence. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 35(4), 887-895.

3. Chengappa, K. R., Levine, J., Gershon, S., Mallinger, A. G., Hardan, A., Vagnucci, A., … & Kupfer, D. J. (2000). Inositol as an add‐on treatment for bipolar depression. Bipolar disorders, 2(1), 47-55.

4. Ciranna, Á. (2006). Serotonin as a modulator of glutamate-and GABA-mediated neurotransmission: implications in physiological functions and in pathology. Current neuropharmacology, 4(2), 101-114.

5. Ebrahimi, E., Khayati Motlagh, S., Nemati, S., & Tavakoli, Z. (2012). Effects of magnesium and vitamin B6 on the severity of premenstrual syndrome symptoms. J Caring Sci, 1(4), 183-9.

6. Ferguson, J. M. (2001). SSRI antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin Psychiatry, 3(1), 22-27.

7. Harvey, B. H., Brink, C. B., Seedat, S., & Stein, D. J. (2002). Defining the neuromolecular action of myo-inositol: application to obsessive–compulsive disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry,26(1), 21-32.

8. Jenkins, T. A., Nguyen, J. C., Polglaze, K. E., & Bertrand, P. P. (2016). Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain axis. Nutrients, 8(1), 56.

9. Kennedy, D. O., & Wightman, E. L. (2011). Herbal extracts and phytochemicals: plant secondary metabolites and the enhancement of human brain function. Advances in Nutrition: An International Review Journal, 2(1), 32-50.

10. Levine, J. (1997). Controlled trials of inositol in psychiatry. European neuropsychopharmacology, 7(2), 147-155.

11. Masoumi, S. Z., Ataollahi, M., & Oshvandi, K. (2016). Effect of Combined Use of Calcium and Vitamin B6 on Premenstrual Syndrome Symptoms: A Randomized Clinical Trial. Journal of caring sciences, 5(1), 67.

12. Mukai, T., Kishi, T., Matsuda, Y., & Iwata, N. (2014). A meta‐analysis of inositol for depression and anxiety disorders. Human Psychopharmacology: Clinical and Experimental, 29(1), 55-63.

13. National Collaborating Centre for Mental Health (UK. (2010). Depression: the treatment and management of depression in adults (updated edition). British Psychological Society.

14. Preskorn, S. H., Ross, R., & Stanga, C. Y. (2004). Selective serotonin reuptake inhibitors. In Antidepressants: Past, present and future (pp. 241-262). Springer Berlin Heidelberg.

15. World Health Organization. (2016). Depression (Fact sheet). Retrieved from

16. Wyatt, K. M., Dimmock, P. W., Jones, P. W., & O’Brien, P. S. (1999). Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. Bmj, 318(7195), 1375-1381.

Clinical Contributor

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Connie Shoemaker, ND

Connie Shoemaker, ND

“Educating Sanesco’s clients is the culmination of a life’s work.” Beginning when she left the hospital environment to manage a functional laboratory, Genova Diagnostics (formerly Great Smokies Laboratories) in 1987, Dr. Connie Shoemaker has continued to increase her knowledge of herbs and biochemistry as a journey of love. With her bachelor’s in science from Western Carolina University, she had worked in hospital laboratories for the first twelve years of her career. Then, personal health challenges led her to discover a new approach to her health and a determination to share it with others. In 1991, she began teaching and educating innovative practitioners in the U.S. and internationally as a manager of marketing, sales, and customer service.

The addition of her Doctor of Naturopathy degree to her existing knowledge base expanded her knowledge and her respect for a more natural approach to healing through balance. At Sanesco, she initially served to oversee technical development of products and services.

Now, she educates Sanesco’s clients on application of the CSM™ model for their specific patients and how to integrate the CSM™ model with other modalities they offer in their practice. In her personal life, Connie educates private clients on various health topics.

Disclaimer: The information provided is only intended to be general educational information to the public. It does not constitute medical advice. If you have specific questions about any medical matter or if you are suffering from any medical condition, you should consult your doctor or other professional healthcare provider.

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One of our feel-good neurotransmitters; when it is deficient, we can suffer mood disorders, sleep issues and carb cravings.